The invention concerns a composition which contains antibodies against human dendritic cells whose surface has the P-selectin glycoprotein ligand 1 (PSGL-1) with the O-bound glycan structure 6-sulfo N-acetyl lactosamine (6-sulfo LacNAc) 6-sulfo LacNAc (herein also referred to as “slan-DC”) and which can influence the immune response via slan-DCs. Furthermore, the invention concerns the diagnostic and therapeutic use of the composition according to the invention. The composition according to the invention is suited for the use in the field of medicine, pharmacy and in biomedical research.
Faulty regulations of the immune system can lead to serious illnesses which are characterized either by immune deficiency or by excessive immunological reactions against essentially harmless antigens or even the body's own antigens. Serious infections or tumor illnesses are directly linked to an inadequate immune response.
The mechanism of the origin of these illnesses is still not yet elucidated completely; this complicates the development of causal therapies against the named illnesses. It is known that dendritic cells (DCs) are capable of, as a function of the signals which they receive, either activating the immune system or inactivating it. The inactivation of the immune system is also called a state of tolerance which exists relative to a discrete antigen.
DCs are capable of activating the immune system antigen-specifically, i.e., to mediate an immunological reaction against a specific antigen, in that the antigen is presented by activated DCs. When a specific antigen is presented by non-activated DCs, an immunological reaction is prevented against the antigen and even tolerance is induced against the antigen (Janeway, Immunologie (7th edition 2009); chapter 7.26, page 385).
In this way, it is in principle possible to therapeutically treat the aforementioned illnesses by specifically influencing the signals transmitted by the DCs. It is problematic in this context that DCs are not of a uniform cell population and different subpopulations of the DCs are suited differently well to cause a relief of the clinical picture via therapeutically given substances which influence the signals of the DCs. This requires systems which bind specifically and with high affinity to dendritic cells but not to other cells.
WO 2009/061966 discloses an antibody which is also referred to as DEC-205 and which specifically binds human DCs and epithelial cells.
EP 1 078 060 B1 discloses antibodies which are directed against DCs. One of the disclosed antibodies is the monoclonal IgM antibody “M-DC8” which binds specifically to a defined subpopulation of the DCs. On account of the specific bond of the antibody M-DC8 to this subpopulation of the DCs, they were initially named “M-DC8 DC” (Schakel et al., European J. Immunol., 1998, 28, 4084-93). It was later found that this subpopulation is characterized in that on the surface of the DC the P-selectin glycoprotein ligand 1 (PSGL-1) comprises the O-bound glycan structure 6-sulfo N-acetyl lactosamine (6-sulfo LacNAc, “slan”) (Schäkel et al., Immunity, 2002, 17, 289-301; Wehner et al., Int J Cancer. 2009, 15, 358-66). Hence, this subpopulation of the DCs was called from this time on “slan-DC” (Schäkel et al., Immunity, 2006, 24, 767-77). It was found that this subpopulation is particularly suitable for influencing the immune system.
A further monoclonal IgM antibody is known which binds specifically to slan-DC and also is referred to as DD2 (Schäkel et al., Immunity, 2002, 17, 289-301).
Handling is a problem for a therapeutic use of IgM antibodies in monoclonal form. IgM antibodies cannot be separated with certainty from small virus particles because of their high molecular weight. Their bad solubility complicates their purification, storage and application as a medicament. Only IgM antibodies in the form of antibody fragments can be used, in particular single chain antibodies, which exhibit a satisfactory binding affinity of a single monomer.
EP 1 078 060 B1 discloses furthermore the therapeutic use of the antibodies which are directed against DCs for targeting target cells. In this context, a recruitment of the target cells to the DCs is enabled by bispecific antibodies which are directed against a surface antigen on DCs and against a surface antigen on target cells, respectively. In particular tumor cells are to be bound to DCs by this implementation in order to cause the admission of the tumor cell. Antigen epitopes of the tumor cells or in general of the target cells are presented on the surface of the DIXs in this way and are intended to cause a specific immune response against the target cells. It is critical in this context that for triggering this immune response against the target cells an additional stimulus is necessary which leads to the activation of the DCs. With the currently known methods in which a stimulus (herein also “co-stimulus” because it is applied always in combination with the antibody) is administered separately and binds e.g. on pattern recognition receptors (PRR) on DCs and thereby activates the DCs, no specific transport of this stimulus to DCs can be generated. A large amount of this stimulus must therefore be administered systemically in order to achieve an effect. This systemic administration has the disadvantage that thereby DCs are not exclusively influenced but also other cells of the immune system may be affected and activated by the stimuli; this leads to undesirable side reactions. When, on the other hand, too little stimulus is administered, DCs are not activated enough and cannot provide the desired effect but cause even the opposite effect, induce an induction of peripheral tolerance.
To mediate tolerance via DCs, the DCs must be present in the inactivated state; a concurrent administration of a co-stimulus is not carried out. In this context, on account of the huge number of possible antigens, it is of great importance to provide therapy systems that enable the targeted transport of different antigens to DCs with low production expenditure.
Object of the invention is to provide a therapy system that is suitable for transporting co-stimuli that activate DCs together with the antigen in a targeted fashion to slan-DCs and that enable with low production expenditure the targeted transport of numerous different antigens to slan-DCs. Furthermore, it is an object of the invention to provide antibodies which are suitable for the use in such therapy systems.